U.S. patent number 5,985,325 [Application Number 09/086,831] was granted by the patent office on 1999-11-16 for rapamycin formulations for oral administration.
This patent grant is currently assigned to American Home Products Corporation. Invention is credited to Arwinder S. Nagi.
United States Patent |
5,985,325 |
Nagi |
November 16, 1999 |
Rapamycin formulations for oral administration
Abstract
This invention provides rapamycin solid dosage unit which
comprises a core and a sugar overcoat, said sugar overcoat
comprising rapamycin, one or more sugars, and one or more
binders.
Inventors: |
Nagi; Arwinder S. (Thiells,
NY) |
Assignee: |
American Home Products
Corporation (Madison, NJ)
|
Family
ID: |
26728896 |
Appl.
No.: |
09/086,831 |
Filed: |
May 29, 1998 |
Current U.S.
Class: |
424/482; 424/122;
424/464; 424/474; 424/475; 424/479; 424/480 |
Current CPC
Class: |
A61K
31/436 (20130101); A61K 9/2086 (20130101) |
Current International
Class: |
A61K
9/20 (20060101); A61K 31/436 (20060101); A61K
31/4353 (20060101); A61K 009/32 (); A61K 031/435 ();
A61K 031/71 () |
Field of
Search: |
;424/464,465,474,475,479,480,482,490,493,497,122 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
|
|
|
|
|
|
|
0525960 |
|
Feb 1993 |
|
EP |
|
0722720 |
|
Jul 1996 |
|
EP |
|
Other References
Derwent Assession No. 1987-318728..
|
Primary Examiner: Harrison; Robert H.
Attorney, Agent or Firm: Milowsky; Arnold S.
Parent Case Text
This application claims the benefit of U.S. Provisional Application
No. 60/050,954, filed Jun. 13, 1997.
Claims
What is claimed:
1. A rapamycin solid dosage unit which comprises a tablet core and
a sugar overcoat; said sugar overcoat comprises
a) rapamycin in an amount from about 0.05-20 mg
b) sucrose in a range from about 50-99% weight of the sugar
overcoat
c) povidone in a range from about 0.2-1.0% weight of the sugar
overcoat, and
d) microcrystalline cellulose in a range from about 0.1-3.0% weight
of the sugar overcoat.
2. The dosage unit according to claim 1, wherein the povidone is
contained as about 0.5% weight of said sugarcoat.
3. The dosage unit according to claim 2, wherein the
microcrystalline cellulose as about 1% weight of said
sugarcoat.
4. The dosage unit according to claim 1, wherein
(a) rapamycin is contained in an amount of about 0.5 mg,
(b) sucrose is contained in a range from about 95-99% weight of
said sugar overcoat
(c) povidone is contained as about 0.5% weight of said sugar
overcoat, and
(d) microcrystalline cellulose is contained as about 1% weight of
said sugar overcoat.
5. The dosage unit according to claim 1, wherein
(a) rapamycin is contained in an amount of about 1 mg,
(b) sucrose is contained in a range from about 94-99% weight of
said sugar overcoat
(c) povidone is contained as about 0.5% weight of said sugar
overcoat, and
(d) microcrystalline cellulose is contained as about 1% weight of
said sugar overcoat.
6. The dosage unit according to claim 1, wherein
(a) rapamycin is contained in an amount of about 3 mg,
(b) sucrose is contained in a range from about 90-99% weight of
said sugar overcoat
(c) povidone is contained as about 0.5% weight of said sugar
overcoat, and
(d) microcrystalline cellulose is contained as about 1% weight of
said sugar overcoat.
7. The dosage unit according to claim 1, wherein
(a) rapamycin is contained in an amount of about 5 mg,
(b) sucrose is contained in a range from about 85-98% weight of
said sugar overcoat
(c) povidone is contained as about 0.5% weight of said sugar
overcoat, and
(d) microcrystalline cellulose is contained as about 1% weight of
said sugar overcoat.
8. The dosage unit according to claim 1, wherein
(a) rapamycin is contained in an amount of about 7.5 mg,
(b) sucrose is contained in a range from about 80-97% weight of
said sugar overcoat
(c) povidone is contained as about 0.5% weight of said sugar
overcoat, and
(d) microcrystalline cellulose is contained as about 1% weight of
said sugar overcoat.
9. The dosage unit according to claim 1, wherein
(a) rapamycin is contained in an amount of about 10 mg,
(b) sucrose is contained in a range from about 75-96% weight of
said sugar overcoat
(c) povidone is contained as about 0.5% weight of said sugar
overcoat, and
(d) microcrystalline cellulose is contained as about 1% weight of
said sugar overcoat.
Description
This invention relates to formulations containing rapamycin, or
pharmaceutically acceptable salts of rapamycin, which are useful in
oral administrations for inducing immunosuppression and for
treating transplantation rejection, host vs. graft disease,
autoimmune diseases, diseases of inflammation, solid tumors, fungal
infections, adult T-cell leukemia/lymphomas and hyperproliferative
vascular disorders.
BACKGROUND OF THE INVENTION
Rapamycin is a macrolide antibiotic produced by Streptomyces
hygroscopicus which was discovered first for its properties as an
antifungal agent. It adversely affects the growth of fungi such as
Candida albicans and Microsporum gypseum. Rapamycin, its
preparation and its antibiotic activity were described in U.S. Pat.
No. 3,929,992, issued Dec. 30, 1975 to Surendra Sehgal et al. In
1977 Martel, R. R. et al. reported on immunosuppressive properties
of rapamycin against experimental allergic encephalitis and
adjuvant arthritis in the Canadian Journal of Physiological
Pharmacology, 55, 48-51 (1977). In 1989, Calne, R. Y. et al. in
Lancet, 1989, no. 2, p. 227 and Morris, R. E. and Meiser, B. M. in
Medicinal Science Research, 1989, No. 17, P. 609-10, separately
reported on the effectiveness of rapamycin in inhibiting rejection
in vivo in allograft transplantation. Numerous articles have
followed describing the immunosuppressive and rejection inhibiting
properties of rapamycin, and clinical investigations have begun for
the use of rapamycin in inhibiting rejection in transplantation in
man.
Rapamycin alone (U.S. Pat. No. 4,885,171) or in combination with
picibanil (U.S. Pat. No. 4,401,653) has been shown to have
antitumor activity. R. Martel et al. [Can. J. Physiol. Pharmacol.
55, 48 (1977)] disclosed that rapamycin is effective in the
experimental allergic encephalomyelitis model, a model for multiple
sclerosis; in the adjuvant arthritis model, a model for rheumatoid
arthritis; and effectively inhibited the formation of IgE-like
antibodies.
The inmmunosuppressive effects of rapamycin have been disclosed in
FASEB 3, 3411 (1989). Cyclosporin A and FK-506, other macrocyclic
molecules, also have been shown to be effective as
immunosuppressive agents, therefore useful in preventing transplant
rejection [FASEB 3, 3411 (1989); FASEB 3, 5256 (1989); R. Y. Calne
et al., and Lancet 1183 (1978).
Rapamycin has been shown to inhibit transplantation rejection in
mammals [U.S. Pat. No. 5,100,899]. Rapamycin, its derivatives and
prodrugs have also been shown to be useful in treating pulmonary
inflammation [U.S. Pat. No. 5,080,899], systemic lupus
erythematosis [U.S. Pat. No. 5,078,899], immunoinflammatory skin
disorders, such as psoriasis [U.S. Pat. No. 5,286,730],
immunoinflammatory bowel disorders [U.S. Pat. No. 5,286,731],
ocular inflammation [U.S. Pat. No. 5,387,589], hyperproliferative
vascular disorders, such as restenosis [U.S. Pat. Nos. 5,512,781
and 5,288,711], carcinomas [U.S. Pat. No. 5,206,018 and 4,885,171],
and cardiac inflammatory disease [U.S. Pat. No. 5,496,832]; and in
preventing the onset of insulin dependent diabetes mellitus [U.S.
Pat. No. 5,321,009]. Additionally, rapamycin has been shown to be
useful in treating adult T-cell leukemia/lymphoma [European Pat.
No. Application 525,960 A1], and in treating ocular inflammation
[U.S. Pat. No. 5,387,589].
Because of its poor oil and water solubility, only a few
formulations of rapamycin have proven satisfactory. U.S. Pat. Nos.
5,516,770 and 5,530,006 disclose intravenous rapamycin
formulations, and U.S. Pat. Nos. 5,536,729 and 5,559,121 disclose
liquid oral rapamycin formulations.
Mono- and diacylated derivatives of rapamycin (esterified at the 28
and 43 positions) have been shown to be useful as antifungal agents
(U.S. Pat. No. 4,316,885) and used to make water soluble prodrugs
of rapamycin (U.S. Pat. No. 4,650,803). Recently, the numbering
convention for rapamycin has been changed; therefore according to
Chemical Abstracts nomenclature, the esters described above would
be at the 31- and 42-positions. U.S. Pat. No. 5,118,678 discloses
carbamates of rapamycin that are useful as immunosuppressive,
anti-inflammatory, antifungal, and antitumor agents. U. S. Pat. No.
5,100,883 discloses fluorinated esters of rapamycin. U. S. Pat. No.
5,118,677 discloses amide esters of rapamycin. U. S. Pat. No.
5,130,307 discloses aminoesters of rapamycin. U. S. Pat. No.
5,117,203 discloses sulfonates and sulfamates of rapamycin. U.S.
Pat. No. 5,194,447 discloses sulfonylcarbamates of rapamycin.
The primary immunosuppressive agent presently used for inhibiting
rejection in the allograft transplantation of organs in man is
SANDIMMUNE (cyclosporine). Cyclosporine is a cyclic polypeptide
consisting of 11 amino acids. The intravenous injectable
formulation of SANDIMMUNE (IV) is a sterile ampoule containing, per
ml, 50 mg of cyclosporine, 650 mg of Cremophor.RTM. EL and alcohol
Ph Helv. (32.9% by volume) (under nitrogen). For administration
this mixture is diluted further with 0.9% Sodium Chloride Injection
or 5% Dextrose Injection before use. (Physicians' Desk Reference,
45th ed., 1991, pp. 1962-64, Medical Economics Company, Inc.) The
macrolide molecule designated FK506, which has certain structural
similarities to rapamycin, is also currently undergoing clinical
investigation for inhibiting rejection in allograft organ
transplantation in man. FK506 is isolated from Streptomyces
tsuskubaensis and is described in U.S. Pat. No. 4,894,366 to
Okuhara et al., issued Jan. 16, 1990 R. Venkataramanan et al., in
Transplantation Proceedings, 22, No. 1, Suppl., 1 pp 52-56
(February 1990), report that the intravenous injectable formulation
of FK506 is provided as a 10 mg/ml solution of FK506 in
polyoxyethylated castor oil (HCO-60, a surfactant) and alcohol. The
intravenous preparation must be diluted with saline or dextrose and
administered as an infusion for 1 to 2 hours.
The Physicians' Desk Reference (45th ed., 1991, p. 2119, Medical
Economics Company, Inc.) lists SANDIMMUNE (cyclosporine) as
available in 25 mg and 100 mg strength capsules and as an oral
solution in 50 ml bottles. The 25 mg capsules contain 25 mg
cyclosporine, USP, and alcohol, USP dehydrated, at a maximum of
12.7% by volume. The 100 mg capsules contain cyclosporine, USP, 100
mg and alcohol, USP dehydrated, at a maximum 12.7% by volume.
Inactive ingredients in the oral capsules are corn oil, gelatin,
glycerol, Labrafil M 2125 CS (polyoxyethylated glycolysed
glycerides), red iron oxide, sorbitol, titanium dioxide, and other
ingredients. The oral solution is available in 50 mg bottles
containing cyclosporine, USP, 100 mg and Ph. Helv. alcohol at 12.5%
by volume dissolved in olive oil, Ph. Helv./Labrafil M 1944 CS
(polyoxyethylated oleic glycerides) vehicle which must be diluted
further with milk, chocolate milk or orange juice before oral
administration.
IMURAN (azathioprine, available from Burroughs Wellcome Co.,
Research Triangle Park, N.C.) is another orally administered
immunosuppressive agent prescribed alone or in conjunction with
other immunosuppressive agents. The Physicians' Desk Reference
(45th ed., 1991, pp. 785-787, Medical Economics Company, Inc.)
lists azathioprine as 6-[1-methyl-4-nitroimidazol-5-yl)thio]purine,
which is provided for oral administration in scored tablets
containing 50 mg azathioprine and the inactive ingredients lactose,
magnesium stearate, potato starch, povidone, and stearic acid.
DESCRIPTION OF THE INVENTION
Methods of drug delivery are designed to deliver an acceptable
dosage of the medication to the patient. In the case of oral
formulations, it is highly desirable to provide a dosage form which
meets this criteria and which can be effectively administered,
preferably self-administered, in either clinical or non-clinical
situations.
The present invention concerns formulations useful in the oral
administration of rapamycin. Rapamycin has been shown to possess
immunosuppressive, antirejection, antifungal and antiinflammatory
activity in vivo and to inhibit thymocyte proliferation in vitro.
Therefore, these formulations are useful in the treatment or
inhibition of transplantation rejection such as kidney, heart,
liver, lung, bone marrow, pancreas (islet cells), cornea, small
bowel, and skin allografts, and heart valve xenografts; in the
treatment or inhibition of graft vs. host disease; in the treatment
or inhibition of autoimmune diseases such as lupus, rheumatoid
arthritis, diabetes mellitus, myasthenia gravis, and multiple
sclerosis; and diseases of inflammation such as psoriasis,
dermatitis, eczema, seborrhea, inflammatory bowel disease,
pulmonary inflammation (including asthma, chronic obstructive
pulmonary disease, emphysema, acute respiratory distress syndrome,
bronchitis, and the like), and eye uveitis.
Rapamycin has also been shown to have antitumor, antifungal, and
antiproliferative activities. The formulations of this invention
therefore also useful in treating solid tumors, including sarcomas
and carcinomas, such as astrocytomas, prostate cancer, breast
cancer, small cell lung cancer, and ovarian cancer; adult T-cell
leukemia/lymphoma; fungal infections; and hyperproliferative
vascular diseases such as restenosis and atherosclerosis.
The present invention, also provides formulations for use in
inducing immunosuppression in a mammal in such need.
In general, the formulations of this invention provides an oral
tablet dosage form of rapamycin comprising a core which is
overcoated with rapamycin, and a sugar coat containing one or more
sugars and one or more binders. It is preferred that such dosage
tablets contain 0.05-20 mg rapamycin, with it being more preferred
that such tablet will contain 0.5-10 mg rapamycin.
The sugar used in the production of the sugar overcoat described in
this invention is a sugar product, such as sucrose, derived from
beet or cane sources or starch, saccharide, or polysaccharide
converted sources, which are considered suitable for preparing the
sugar overcoat. When used in preparing the solid dosage form of
this invention, it is preferred that the sugar is sucrose.
When binders are used in preparing the rapamycin oral dosage
tablets, these can include gum acacia, tragacanth, stearic acid,
gelatin, casein, lecithin (phosphatides), carboxymethylcellulose
calcium, carboxymethylcellulose sodium, methylcellulose,
hydroxyethylcellulose, hydroxypropylcellulose,
hydroxypropylmethycellulose phthalate, methyacrylate,
microcrystalline cellulose, noncrystalline cellulose,
polyvinylpyrrolidone (povidone, PVP), cetostearyl alcohol, cetyl
alcohol, cetyl esters wax, dextrates, dextrin, lactose, dextrose,
glyceryl monooleate, glyceryl monostearate, glyceryl
palmitostearate, polyoxyethylene alkyl ethers, polyethylene
glycols, polyoxyethylene castor oil derivatives, polyoxyethylene
stearates, polyvinyl alcohol, and sorbitan fatty acid esters.
The dosage tablets described herein provide rapamycin contained in
a sugar overcoat that has been overcoated onto a core. The core can
either be pharmaceutically inert or can contain a pharmaceutically
active agent. As used in describing this invention the term "sugar
overcoat" refers to the rapamycin, sugar, and binder which coat the
core.
The following provides a preferred formulation for the sugar
overcoat of a solid dosage tablet containing 0.05-20 mg
rapamycin.
a) rapamycin in an amount from about 0.05-20 mg
b) sucrose in a range from about 50-99% weight of the sugar
overcoat
c) one or more binders in a range from about 0.1-10% weight of the
sugar overcoat
In the formulations described in this invention, the quantities of
the ingredients specified as percentages will vary according to the
weight of the sugar overcoat. The sugar overcoat described in this
invention will typically weigh about 50-200 mg. Therefore in the
above formulation, the quantity of sucrose would be about 25 mg
(about 50% weight of the sugar overcoat) for a 50 mg sugar overcoat
containing 20 mg rapamycin and 10% (5 mg) binders. Similarly, the
percent weight of sucrose in the sugar overcoat can comprise
greater than 99% of the sugar overcoat when a 200 mg sugar overcoat
contains 0.05 mg rapamycin and 0.1% (0.2 mg) binders.
The following provides a more preferred formulation for the sugar
overcoat of a solid dosage tablet containing 0.05-20 mg rapamycin,
in which the sugar overcoat contains povidone and microcrystalline
cellulose as binders.
a) rapamycin in an amount from about 0.05-20 mg
b) sucrose in a range from about 50-99% weight of the final
overcoat
c) povidone in a range from about 0.2-1.0 % weight of the final
overcoat
d) microcyrstalline cellulose in a range from about 0.1-3.0 %
weight of the final overcoat
A rapamycin containing oral dosage tablet containing the above
constituents can be prepared according to the following procedure.
In preparing the above formulation, about 40-60 mg water is used in
preparing a 100 mg sugar overcoat; the water is subsequently
removed during processing. Briefly, rapamycin is either milled
using conventional milling techniques, for example with a Fitz or
ball mill, or is micronized using conventional micronizing
techniques, for example with a Trost or jet mill. Milled rapamycin
typically has a 10-400 micron particle size, and micronized
rapamycin typically has a 0.5-10 micron particle size. The required
quantity of water is heated to around 65-70.degree. C. and sucrose
is added, and mixed well until the sucrose is dissolved. The
solution is cooled to about 30-40.degree. C. Povidone is added and
mixed vigorously until dissolved. Rapamycin is added to the mixture
and mixed well to uniformly disperse the rapamycin, Microcrystaline
cellulose is added, and the mixture stirred to provide a uniform
suspension. Additional water is added if necessary and the
suspension is continuously mixed during the coating process. The
mixture is spray coated onto a core in small portions, and air
dried in between portions, until the desired tablet strength is
formed. During the manufacturing process, the majority of the water
is removed, such that approximately less than 5% water remains in
each tablet. Typically less than 2% residual water is present in
each tablet. The rapamycin containing oral dosage tablets can be
optionally coated with a color coat followed by a polish coat if
desirable. The color coat typically contains a sugar such as
sucrose, and a pigment such as titanium dioxide, and the polish
coat contains carnuba wax, which can be applied as a dispersion in
a solvent, such as mineral spirits.
When the core is a pharmaceutically inert core, it is typically a
placebo core which may contain lactose, microcrystalline cellulose,
PEG-6000, and other binders and fillers. The core, can be sealed
with shellac to prevent disintegration from occurring during the
overcoating process. A sucrose coat may also be placed on top of
the shellac coat prior to the overcoating process.
The sugar overcoating described in this invention can be prepared
to typically weigh about 50-200 mg. Using the process described
herein, a 100 mg sugar overcoat containing 0.05-20 mg rapamycin
would be made from the following ingredients according to the
procedure described above:
a) rapamycin in an amount from about 0.05-20 mg
c) sucrose in an amount from about 50-99 mg
d) povidone in an the amount from about 0.2-1.0 mg
e) microcyrstalline cellulose in an amount from about 0.1-3.0
mg
f) water in an amount from 40-60 mg (mostly removed during
processing)
It is contemplated that when the formulations of this invention are
used as an immunosuppressive or antiinflammatory agent, they can be
administered in conjunction with one or more other immunoregulatory
agents. Such other antirejection chemotherapeutic agents include,
but are not limited to azathioprine, corticosteroids, such as
prednisone and methylprednisolone, cyclophosphamide, cyclosporin A,
FK-506, OKT-3, and ATG. By combining one or more of the
formulations of the present invention with such other drugs or
agents for inducing immunosuppression or treating inflammatory
conditions, lesser amounts of each of the agents may be required to
achieve the desired effect. The basis for such combination therapy
was established by Stepkowski whose results showed that the use of
a combination of rapamycin and cyclosporin A at subtherapeutic
doses significantly prolonged heart allograft survival time.
[Transplantation Proc. 23: 507 (1991)].
The dosage requirements may vary the severity of the symptoms
presented and the particular subject being treated. Projected daily
oral dosages of rapamycin would be 0.05-25 mg, with preferred
projected daily doses being 0.5-10 mg when rapamycin is used in
combination therapy, and 1-25 mg when rapamycin is used as
monotherapy. More preferred projected daily doses are 2-5 mg when
rapamycin is used in combination therapy, and 5-15 mg when
rapamycin is used as monotherapy.
Treatment will generally be initiated with small dosages less than
the optimum dose of the compound. Thereafter the dosage is
increased until the optimum effect under the circumstances is
reached. Precise dosages will be determined by the administering
physician based on experience with the individual subject treated.
In general, the formulations of this invention are most desirably
administered at a concentration that will generally afford
effective results without causing any harmful or deleterious side
effects.
The oral dosage tablet formulation of this invention can also be
used to make oral dosage tablets containing derivatives of
rapamycin, including, but not limited to rapamycin esters,
carbamates, sulfates, ethers, oximes, carbonates, the like which
are all well described in the patent literature .
The following provide the preparation and evaluation of
representative examples of rapamycin solid dosage tablets.
EXAMPLE 1
The following shows the preparation and evaluation of a 3.0 mg
rapamycin oral dosage tablet containing a 100 mg sugar
overcoat.
______________________________________ Formula: Ingredients* Amount
______________________________________ Rapamycin 3.06 mg Sucrose
97.41 mg Povidone 0.510 mg Microcrystaline cellulose 1.020 mg Water
54.92 mg ______________________________________ *A 2% overage is
included in these quantities to account for manufacturin
losses.
Manufacturing Directions
1. The water was heated to around 65-70.degree. C., and sucrose was
added and mixed well until dissolved. The solution was cooled to
about 30-40.degree. C.
2. Povidone was added and mixed vigorously until dissolved.
3. Milled or micronized rapamycin was added to the mixture and
mixed well to uniformly disperse the rapamycin.
4. Microcrystaline cellulose was added, and the mixture stirred to
provide a uniform suspension.
5. The resulting solution was spray coated onto a pharmaceutically
inert core portionwise and air dried in between portions.
Evaluation
Six Cynomolgus monkeys, listed below as A-C, were administered the
above formulation at a dose of 3 mg rapamycin per monkey and the
following serum concentrations of rapamycin were determined at the
indicated time after dosing.
______________________________________ Rapamycin Concentration
(nanogram/ml)/Monkey Number Time A B C
______________________________________ 0 hr. 0.00 0.00 0.00 0.25
hr. 4.53 0.00 1.01 0.5 hr. 7.85 0.49 2.26 1.0 hr. 8.43 1.12 4.02 2
hr. 4.51 1.58 4.34 4 hr. 3.94 2.68 2.76 8 hr. 6.50 5.33 6.67 12 hr.
6.01 3.88 5.25 16 hr. 5.31 3.69 5.04 24 hr. 3.94 3.40 4.96
______________________________________
The results obtained demonstrate that serum concentrations of
rapamycin were observed following the administration of a
representative oral dosage tablet of this invention.
EXAMPLE 2
A 0.5 mg rapamycin oral dosage tablet containing a 100 mg sugar
overcoat was prepared according the procedure described in Example
1. The following lists the quantities of ingredients used.
______________________________________ Formula: Ingredients* Amount
______________________________________ Rapamycin 0.510 mg Sucrose
99.96 mg Povidone 0.510 mg Microcrystaline cellulose 1.020 mg Water
54.92 mg ______________________________________ *A 2% overage is
included in these quantities to account for manufacturin
losses.
EXAMPLE 3
A 1.0 mg rapamycin oral dosage tablet containing a 100 mg sugar
overcoat was prepared according the procedure described in Example
1. The following lists the quantities of ingredients used.
______________________________________ Formula: Ingredients* Amount
______________________________________ Rapamycin 1.02 mg Sucrose
99.45 mg Povidone 0.510 mg Microcrystaline cellulose 1.020 mg Water
54.92 mg ______________________________________ *A 2% overage is
included in these quantities to account for manufacturin
losses.
EXAMPLE 4
A 5.0 mg rapamycin oral dosage table containing a 100 mg sugar
overcoat was prepared according the procedure described in Example
1. The following lists the quantities of ingredients used.
______________________________________ Formula: Ingredients* Amount
______________________________________ Rapamycin 5.10 mg Sucrose
95.37 mg Povidone 0.510 mg Microcrystaline cellulose 1.020 mg Water
54.92 mg ______________________________________ *A 2% overage is
included in these quantities to account for manufacturin
losses.
EXAMPLE 5
A 7.5 mg rapamycin oral dosage tablet containing a 100 mg sugar
overcoat was prepared according the procedure described in Example
1. The following lists the quantities of ingredients used.
______________________________________ Formula: Ingredients* Amount
______________________________________ Rapamycin 7.65 mg Sucrose
92.82 mg Povidone 0.510 mg Microcrystaline cellulose 1.020 mg Water
54.92 mg ______________________________________ *A 2% overage is
included in these quantities to account for manufacturin
losses.
EXAMPLE 6
A 10 mg rapamycin oral dosage tablet containing a 100 mg sugar
overcoat was prepared according the procedure described in Example
1. The following lists the quantities of ingredients used.
______________________________________ Formula: Ingredients* Amount
______________________________________ Rapamycin 10.2 mg Sucrose
90.27 mg Povidone 0.510 mg Microcrystaline cellulose 1.020 mg Water
54.92 mg ______________________________________ *A 2% overage is
included in these quantities to account for manufacturin
losses.
* * * * *